A giant lobular thoracic ganglioneuroma cause skeletal erosion: A case report and literature review

Rationale: Ganglioneuroma (GN) is a rare tumor that originates from neural crest cells and can manifest in any location along the sympathetic chain. It typically exhibits a circular or oval shape and does not invade the surrounding tissue destructively and the enormous lobular appearance and erosion of adjacent skeletal tissues are extremely infrequent among GN. Patient concerns: A 15-year-old girl presented to our thoracic surgery clinic with a large intrathoracic mass that was incidentally discovered on a chest X-ray. Further imaging with computed tomography and magnetic resonance imaging revealed a lobular profile and an aggressive growth pattern of the tumor, which destroyed the vertebral and rib bones. A tissue sample obtained by needle biopsy was subjected to histopathological analysis, which confirmed the diagnosis of a GN. Diagnosis: Thoracic (posterior mediastinal) GN and Hashimoto’s thyroiditis. Interventions: After thoracoscopic exploration, a thoracotomy was performed to excise the mass. Outcomes: The patient recovered well after surgery, had no major complications, and was discharged without any issues. Further follow-up is necessary to clarify the medium to long-term outcome. Lessons: Based on existing reports, thoracic GN rarely erodes adjacent bone tissue. By examining previously reported cases, we speculate that the lobular morphology of the tumor may be linked to the more aggressive biological behavior of GN. We also discovered that female patients may be more susceptible to bone erosion. However, further research and additional cases are required to confirm these potential associations.


Introduction
Ganglioneuroma (GN) is an uncommon, benign tumor that arises from neural crest cells in the sympathetic ganglia or adrenal medulla. Typically, GNs present in the retroperitoneum, posterior mediastinum, or adrenal gland, and occasionally in atypical locations such as intracranial and ureter. [1][2][3] GNs are typically oval or round in shape and do not destructively erode surrounding structures. [4] In this report, we describe a unique instance of a gigantic lobular GN in the thoracic cavity that caused neighboring rib deformity and erosion of nearby vertebral bodies. The guardians of the patient provided consent for the publication of the report, and both the patient and her mother signed the informed consent form.

Timeline
Important milestones related to our diagnoses and interventions are exhibit in the Table 1.

Case presentation
A 15-year-old girl was found to have a large mass in her right chest during a routine chest X-ray examination. She was admitted to the thoracic surgery department with her mother and had no apparent symptoms or abnormal physical examination results. Her medical history was healthy, with no history of trauma, surgery, or special family history, and a normal menstrual history. Laboratory tests showed elevated levels of FT4, AntiTPO, and TGAB (16.51 pmol/L, 56.33 IU/mL, and 1032.34 IU/mL, respectively). Combining the patient's thyroid ultrasound results, she was diagnosed with Hashimoto's thyroiditis. No other abnormalities were found in the rest of the laboratory tests.
Subsequently, a chest computed tomography (CT) scan (including plain and enhanced scans) was performed, which revealed a large low-density lobular mass in the right posterior mediastinum, with bone destruction in the adjacent vertebra and deformed thickening in the right 6th to 8th ribs. After enhancement, the mass showed mild to moderate enhancement. Meanwhile, a ribbon-like shadow was found in the lower lobe of the right lung, with bronchial narrowing, and the thyroid gland was found to be enlarged with uneven density. Based on the CT data, the imaging department suspected that the mass was a neurogenic tumor, but no clear diagnosis could be made. After reviewing the literature, we hypothesized that the diagnosis of ganglioneuroma is more probable. However, it is crucial to differentiate it from neuroblastoma, ganglioneuroblastoma intermixed, and other neurogenic tumors.
To further clarify the diagnosis and determine whether the tumor invaded the spinal canal, a thoracic MRI scan was performed. The mass showed slightly low signal intensity on T1-weighted images and slightly high signal intensity with linear low signals on T2-weighted images. After enhancement, most of the lesions showed mild to moderate uneven enhancement with obvious enhancement around the lesions. Based on the MRI findings, the imaging department considered the mass to be a ganglioneuroma (Fig. 1).
After excluding surgical contraindications, surgical treatment was performed on the patient. Due to the large size of the tumor, thoracoscopy was first used to explore the lesion and evaluate the feasibility of tumor resection under thoracoscopy. A large lobular mass with intact capsule was seen in the thoracic cavity, due to the large volume of the tumor and its close adhesion to the ribs, right thoracotomy was performed midway through the surgery to remove the tumor. The tumor was divided into three parts for resection (Fig. 2). Considering the risk of complications such as cerebrospinal fluid leakage, The resection was extended to the visible lesion in the intervertebral foramen of the 6th and 7th thoracic vertebrae on the right side. The patient did not experience any significant surgical complications and recovered well. The routine pathological examination of the specimen after surgery was consistent with the results of the needle biopsy (Fig. 3). The patient was smoothly discharged on the tenth day of hospitalization. Currently (3 weeks after operation), there have been no reports of any special discomfort from the patient during telephone follow-up.

Patient perspective
The patient rejected to share her perspective or experience.

Discussion
Neuroblastic tumors encompass neuroblastoma, ganglioneuroblastoma (nodular or intermixed), and ganglioneuroma. The Table 1 Timeline.  International Neuroblastoma Pathology Classification identifies ganglioneuroblastoma intermixed and GN as the mature part of neuroblastic tumors. [5][6][7] GN is a benign tumor characterized by slow development and lack of invasion. It originates from neural crest cells and is most commonly found in the abdomen/pelvis (66.2%), [8] post mediastinum, and adrenal glands. [1] Thoracic GN usually does not cause symptoms, but in rare cases, it may cause general symptoms such as chest tightness, wheezing, and coughing. If the tumor occurs near the thoracic vertebra, it may cause scoliosis. In cases where the tumor extends to the intervertebral foramina and compresses the spinal cord, it can cause the neurological symptom. [9,10] The majority of intrathoracic GNs present with a regular circular or oval shape and rarely invade surrounding tissues. [4,11] However, in this particular case, the thoracic GN exhibited an extremely rare appearance with massive lobulation and erosion of the adjacent vertebral bodies and ribs, and as the tumor continued to compress and stimulate the surrounding tissues, varying degrees of bone proliferation occurred in the adjacent ribs and vertebrae. Only a few similar cases have been reported in the previous literature. [12][13][14] In light of these findings, we conducted a review of the literature on intrathoracic GNs from 1990 to the present, to identify commonalities and characteristics of this unusual and destructive growth pattern in intrathoracic GNs. The inclusion criteria are as follows:

Date Milestones
1) Literature related to primary intrathoracic GN.
The exclusion criteria are shown below: 1) Missing critical information about the patient; 2) Secondary intrathoracic GN; 3) Cross-regional GNs, such as extending into the cervical spine or abdomen; 4) GNs in other sites.
We collected a total of 22 articles and 71 cases (including the present case). The clinical data of the patients are shown in Table 2, with a median age of 11 and an average age of 21. The sample included 44 females (62.9%) and 26 males (37.1%), resulting in a female-to-male ratio of 1.7:1. Intrathoracic GN appears to be more common in female patients, which is consistent with previous findings. 8 Excluding cases with missing data, 6 cases (9.7%) were identified as having lobular GN, while the rest had regular round or oval GN shapes.
Among the thoracic GN cases, 6 (9.5%) were found to have caused bone erosion, including 3 cases of lobular GN and 3 of regular GN. All six patients were female, with a median age of 11 and an average age of 11. Additionally, 6 cases (9.7%) resulted in rib deformity. In the lobular thoracic GN cases, 3 (50%) caused bone erosion, while in the regular thoracic GN cases, 3 (4.6%) caused bone erosion. After statistical analysis (using R software version 4.2.2), we found a significant difference in the incidence of bone erosion between regular and lobular thoracic GN cases (Fisher's exact test, P = .006 < .05, OR = .054, 95% CI: .0045-.56). Patients with lobular GN had a significantly higher probability of bone erosion than those with regular GN. This suggests that the appearance of lobular tumors may be related to bone erosion. Due to the small sample size, however, additional instances and research are required to confirm this link.
In the currently limited sample, the rare and aggressive growth pattern of GN that causes bone erosion was only found in female patients. This indicates that there may be a    [15] 1992 17/F L N/A Regular No No Osterhouse [16] 2002 25/F L 15 × 7 × 3 Regular No Yes Duffy [17] 2005 27/F R N/A N/A No No Velyvis [10] 2005 15/F R 8 × 8 × 2 Regular No Yes Maruyama [18] 2007 74/F R 6.9 × 5.8 × 1.6 Regular No No Ko [19] 2007 53/F R 9 × 4.5 × 10 Regular No No Zhang [20] 2009 3/F L 5.8 × 4.5 × 4.  [23] 2017 12/F L 12 × 12 × 12 Regular No No Jeon [24] 2017 6/M R 4 × 3.5 × 2 Regular No No Lambdin [25] 2018 42/F L 23 × 10 × 10 Regular No No Algazwi [26] 2020 18/F R N/A Regular No No Elnady [27] 2020 17/F L N/A Regular No No Brock [14] 2020 12/F R 10 × 9.1 × 9.5 Regular Yes Yes Aljuboori [28] 2021 30/NA R N/A Regular No No Tiwari [29] 2022 4/F L 3.8 × 2.5 × 2.3 Regular No No (Continued ) www.md-journal.com potential association between this destructive character of GN and patients' gender. Of course, this also requires larger sample sizes and systematic analysis for verification. If these potential associations are validated, clinicians could receive more information to tailor personalized treatments for GN patients with different morphological features and genders. This could lead to better predictions of patient prognosis. For young female patients with lobular GN, GNs are more likely to be aggressive. Therefore, early surgery may be a more suitable treatment option to mitigate the potential risks of long-term follow-ups, such as the risk of the tumor continuing to grow and causing more damage.
Under CT, GN typically presents as a low-density mass with a round or elliptical shape (lower than the density of surrounding muscles), sometimes accompanied by punctate calcification. On enhanced scans, there is usually mild to the moderate enhancement and a delayed enhancement feature. On MRI, GN typically appears as a low signal on T1-weighted images and a high signal on T2-weighted images, sometimes with a "whorl" appearance. This appearance corresponds to the characteristic appearance of GN under a microscope where the interlacing of Schwann cells and collagen fibers is observed. [4,13,32,33] If GN has atypical CT and MRI Findings, the co-existence of malignant components should be considered. [11] The CT and MRI findings, in this case, are consistent with previous reports, but imaging examination revealed that the tumor had an obvious lobular appearance and eroded adjacent bones. These conditions are extremely rare. Kato et al mentioned a case of lobular thoracic GN eroding the vertebral body and causing rib deformity in their study, [13] but the erosion area, in that case, was relatively broad and superficial, while in this case, the erosion of the vertebral body was deeper and more severe. This suggests that in cases where GN erodes bones, their invasiveness may vary in different ways and degrees.
Thoracic GN needs to be differentiated from mediastinal masses such as thymoma, lymphoma, tuberculosis lymphadenitis, neurofibroma, schwannoma, and neuroblastoma. Although imaging examinations can help diagnose GN to a large extent, the final diagnosis still requires histopathological examination due to its low specificity. [34] Sánchez-Galán et al pointed out that the focus of treating GN is on personalized treatment plans. Complete removal of GN should only be considered as a treatment goal if it does not pose significant risks to the patient and surrounding structures. Imaging should be used to determine surgical risk factors and minimize the likelihood of surgical complications in GN surgical planning. It is important to note that incomplete removal may also be a reasonable choice due to the favorable prognosis of these tumors. In certain special cases, non-surgical treatment may be a reasonable option for treating GN. [22] However, for GNs growing beside the thoracic vertebrae, short-term stability may lead clinicians to underestimate the potential damage caused by their long-term growth. Considering that thoracic GNs may cause problems such as scoliosis, spinal cord compression, bone erosion, and bone destruction during growth, we recommend adopting an early surgical resection strategy for thoracic GNs based on the individual characteristics of the patient to avoid the risks brought by long-term follow-up.
In terms of surgical options, thoracoscopy is a safe and efficient procedure for removing thoracic neurogenic tumors. It allows for enhanced visualization of the tumor and its connections and can facilitate a full excision without increasing the complexity or duration of the operation. Using this technique avoids the cosmetic and functional issues associated with a thoracotomy and results in a good cosmetic resection without tumor spillage, [35] If a patient is diagnosed with intrathoracic GN and the tumor is small, with imaging evaluation showing no invasion of the spinal canal, thoracoscopy should be the preferred approach. If during surgery, the tumor is found to have tightly adhered to surrounding tissues or structures, or other factors make it difficult to complete the operation thoracoscopically, conversion to thoracotomy is also a reasonable option. If the tumor is giant, considering the good prognosis of GN with low recurrence rates, [36,37] open surgery for segmental resection of the tumor is a good option, which can reduce damage to the paravertebral nerves and muscles. The use of different surgical methods can avoid damage to important blood vessels, nerves, and organs, and ensure complete exposure of the tumor. At the same time, the use of different surgical methods can reduce the surgical time, making it easier for patients to tolerate the procedure, and allowing the surgeon to conserve energy. This also improves the safety of the surgical process. Giant paraspinal GNs typically affect important organs such as the lungs, kidneys, intestines, and major blood vessels. Postoperative complications include cerebrospinal fluid leakage, paraplegia, intestinal obstruction, perioperative bleeding, pneumothorax, and others. [38] When considering the resection of spinal ganglioneuromas, the surgical approach and extent of resection must be carefully weighed, while also considering the risks of surgical complications. Patients have a favorable long-term prognosis regardless of whether the tumor is excised or not. [39] Currently, the only treatment for GN is surgical resection. However, Tao et al discovered that ganglioneuromas are driven by the activation of the AKT signaling pathway, which promotes cell growth and survival. The researchers also demonstrated that mTOR inhibitors, a class of drugs that target the mTOR pathway downstream of AKT, can effectively inhibit the growth of ganglioneuromas in zebrafish models. These findings suggest that mTOR inhibitors may represent a promising therapeutic strategy for the treatment of ganglioneuromas. [40] If subsequent clinical trials can confirm that mTOR inhibitors can inhibit the growth of GN and reduce the volume of GN tumors in the human body, then targeted therapy to reduce tumor volume before surgery on large-volume GN, while reducing adhesion of the tumor to surrounding tissue, will greatly reduce surgical risks.

Conclusion
Our review of past literature suggests that a lobular appearance may be associated with a more aggressive growth pattern of thoracic GN, which may be more prevalent in young female patients. Therefore, young female patients with lobular GN may require more aggressive surgical strategies to avoid the risks associated with long-term follow-up. However, more cases

Reference
Year Age (yr)/Gender Side Size (cm) Shape Skeletal erosion Rib deformity Nemoto [30] 2022 15/F L N/A Regular No No Chen [31] 2022 57/M L 6.5 × 5.0 × 2  and studies are needed to confirm and investigate these potential associations and the mechanisms behind them.